Heidi Grantz

Decreased Number of Parvalbumin and Cholinergic Interneurons in the Striatum of Individuals with Tourette Syndrome

Corticobasal ganglia neuronal ensembles bring automatic motor skills into voluntary control and integrate them into ongoing motor behavior. A 5% decrease in caudate (Cd) nucleus volume is the most consistent structural finding in the brain of patients with Tourette syndrome (TS), but the cellular abnormalities that underlie this decrease in volume are unclear. In this study the density of different types of interneurons and medium spiny neurons (MSNs) in the striatum was assessed in the postmortem brains of 5 TS subjects as compared with normal controls (NC) by unbiased stereological analyses. TS patients demonstrated a 50%–60% decrease of both parvalbumin (PV)+ and choline acetyltransferase (ChAT)+ cholinergic interneurons in the Cd and the putamen (Pt). Cholinergic interneurons were decreased in TS patients in the associative and sensorimotor regions but not in the limbic regions of the striatum, such that the normal gradient in density of cholinergic cells (highest in associative regions, intermediate in sensorimotor and lowest in limbic regions) was abolished. No significant difference was present in the densities of medium‐sized calretinin (CR)+ interneurons, MSNs, and total neurons. The selective deficit of PV+ and cholinergic striatal interneurons in TS subjects may result in an impaired cortico/thalamic control of striatal neuron firing in TS. J. Comp. Neurol. 518:277–291, 2010.

Increased serum levels of interleukin-12 and tumor necrosis factor-alpha in Tourette’s syndrome

BACKGROUND The hypothesis that common infections can modulate the onset and course of tic disorders and early-onset obsessive-compulsive disorder (OCD) in pediatric populations is longstanding. To date, most investigations have focused on the hypothesis of molecular mimicry and humoral immune responses. This study was carried out to investigate whether cytokines associated with the innate immune response or T cell activation were altered under baseline conditions and during periods of symptom exacerbation. METHODS Forty-six patients with Tourettes syndrome and/or early-onset OCD, aged 7-17 years, and 31 age-matched control subjects participated in a prospective longitudinal study. Ratings of clinical severity and serum were collected at regular intervals, and serum concentrations of 10 cytokines were measured repeatedly. RESULTS Interleukin-12 and tumor necrosis factor alpha concentrations at baseline were elevated in patients compared with control subjects. Both of these markers were further increased during periods of symptom exacerbation. CONCLUSIONS These findings suggest that symptom exacerbations are associated with an inflammatory process propagated by systemic and local cytokine synthesis that might involve the central nervous system. We conclude that, in the future, longitudinal studies of children with neuropsychiatric disorders should examine the involvement of innate and T cell immunity.

Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: A prospective longitudinal study

OBJECTIVE The objective of this blinded, prospective, longitudinal study was to determine whether new group A β hemolytic streptococcal (GABHS) infections are temporally associated with exacerbations of tic or obsessive-compulsive (OC) symptoms in children who met published criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A group of children with Tourette syndrome and/or OC disorder without a PANDAS history served as the comparison (non-PANDAS) group. METHOD Consecutive clinical ratings of tic and OC symptom severity were obtained for 31 PANDAS subjects and 53 non-PANDAS subjects. Clinical symptoms and laboratory values (throat cultures and streptococcal antibody titers) were evaluated at regular intervals during a 25-month period. Additional testing occurred at the time of any tic or OC symptom exacerbation. New GABHS infections were established by throat swab cultures and/or recent significant rise in streptococcal antibodies. Laboratory personnel were blinded to case or control status, clinical (exacerbation or not) condition, and clinical evaluators were blinded to the laboratory results. RESULTS No group differences were observed in the number of clinical exacerbations or the number of newly diagnosed GABHS infections. On only six occasions of a total of 51 (12%), a newly diagnosed GABHS infection was followed, within 2 months, by an exacerbation of tic and/or OC symptoms. In every instance, this association occurred in the non-PANDAS group. CONCLUSIONS This study provides no evidence for a temporal association between GABHS infections and tic/OC symptom exacerbations in children who meet the published PANDAS diagnostic criteria.

Assessment of symptom exacerbations in a longitudinal study of children with Tourette's syndrome or obsessive-compulsive disorder.

OBJECTIVES The severity of tic and obsessive-compulsive (OC) symptoms varies over time. Consequently, how do we, as clinicians, know when a change in symptom severity occurs that falls outside of the normal range of fluctuation? The goal of this study was to describe the level of symptom severity fluctuation over time and to establish an objective, prospective, and quantitative method for identifying symptom exacerbations in children with Tourettes syndrome, obsessive-compulsive disorder (OCD), or both. A second major aim was to assess whether fluctuations in tic and OC symptom severity covaried with one another. METHOD Monthly consecutive Yale Global Tic Severity Scale and Childrens Yale-Brown Obsessive Compulsive Scale scores were prospectively obtained in 64 children diagnosed with Tourettes syndrome and/or OCD for periods ranging from 3 to 39 months. Exacerbation thresholds were estimated by using state-of-the-art bootstrap methods. These thresholds were then independently evaluated by asking two expert clinicians to identify, retrospectively, clinically significant exacerbations based on a review of all available clinical and research records. RESULTS The severity of tic and OC symptoms displayed a high degree of intrasubject variability. Exacerbation thresholds, which incorporated the change score from the previous month and the current symptom score, provided the best agreement with those of expert clinicians. When both tic and OC symptoms were present, they showed a significant degree of covariation. CONCLUSIONS Evidence-based treatments are coming of age. The use of valid, clinician-rated severity scales will likely become a standard part of clinical practice. Bootstrapping methods may provide a quantitative and convenient way to obtain clinically valid thresholds to assess tic and OC symptom exacerbations. This method has the potential to be applied to other symptom domains where exacerbation thresholds are needed.

Development of the Yale Children's Global Stress Index (YCGSI) and Its Application in Children and Adolescents With Tourette's Syndrome and Obsessive-Compulsive Disorder

OBJECTIVE The Yale Childrens Global Stress Index (YCGSI) is a new clinical rating instrument designed to provide objective global clinician ratings of psychosocial stress in studies of children and adolescents. This study was designed to evaluate the psychometric properties of the YCGSI. METHOD Independent ratings of clinical severity and psychosocial stress were obtained at two time points separated by 4 months from 33 subjects with Tourettes syndrome (TS) and/or early-onset obsessive-compulsive disorder (OCD), aged 7 to 17 years, and 25 age-matched control subjects. Parents and children were interviewed separately. Multiple measures of stress were obtained including the YCGSI and the Daily Life Stressors Scale (DLSS). RESULTS Data support the interrater reliability and convergent and divergent validity of the YCGSI. At both time points, children and adolescents with TS and OCD had, on average, experienced significantly more psychosocial stress than did the controls. Cross-sectional ratings of tic and obsessive-compulsive symptom severity did not correlate with the YCGSI, but did correlate with self-report ratings of stress on the DLSS. In contrast, ratings on the YCGSI were associated with clinician ratings of depression. CONCLUSIONS The YCGSI has acceptable psychometric properties. Children and adolescents with TS and OCD appear to be at increased risk of experiencing higher levels of psychosocial stress and adversities compared with their peers in the community. Future studies need to examine the possible differential contributions of distinctive forms of stress on the intramorbid course of these disorders.

Streptococcal Upper Respiratory Tract Infections and Psychosocial Stress Predict Future Tic and Obsessive-Compulsive Symptom Severity in Children and Adolescents with Tourette Syndrome and Obsessive-Compulsive Disorder

BACKGROUND One goal of this prospective longitudinal study was to identify new group A beta-hemolytic streptococcal infections (GABHS) in children and adolescents with Tourette syndrome (TS) and/or obsessive-compulsive disorder (OCD) compared with healthy control subjects. We then examined the power of GABHS infections and measures of psychosocial stress to predict future tic, obsessive-compulsive (OC), and depressive symptom severity. METHODS Consecutive ratings of tic, OC, and depressive symptom severity were obtained for 45 cases and 41 matched control subjects over a 2-year period. Clinical raters were blinded to the results of laboratory tests. Laboratory personnel were blinded to case or control status and clinical ratings. Structural equation modeling for unbalanced repeated measures was used to assess the sequence of new GABHS infections and psychosocial stress and their impact on future symptom severity. RESULTS Increases in tic and OC symptom severity did not occur after every new GABHS infection. However, the structural equation model found that these newly diagnosed infections were predictive of modest increases in future tic and OC symptom severity but did not predict future depressive symptom severity. In addition, the inclusion of new infections in the model greatly enhanced, by a factor of three, the power of psychosocial stress in predicting future tic and OC symptom severity. CONCLUSIONS Our data suggest that a minority of children with TS and early-onset OCD were sensitive to antecedent GABHS infections. These infections also enhanced the predictive power of current psychosocial stress on future tic and OC symptom severity.

A Randomized Controlled Trial of an Integrated Brain, Body, and Social Intervention for Children With ADHD

Objective: This study evaluated the efficacy of an Integrated Brain, Body, and Social (IBBS) intervention for children with ADHD. Treatment consisted of computerized cognitive remediation training, physical exercises, and a behavior management strategy. Method: Ninety-two children aged 5 to 9 years with ADHD were randomly assigned to 15 weeks of IBBS or to treatment-as-usual. Primary outcome measures included blinded clinician ratings of ADHD symptoms and global clinical functioning. Secondary outcome measures consisted of parent and teacher ratings of ADHD and neurocognitive tests. Results: No significant treatment effects were found on any of our primary outcome measures. In terms of secondary outcome measures, the IBBS group showed significant improvement on a verbal working memory task; however, this result did not survive correction for multiple group comparisons. Conclusion: These results suggest that expanding cognitive training to multiple domains by means of two training modalities does not lead to generalized improvement of ADHD symptomatology.

Individualized Assessments in Treatment Research: An Examination of Parent-Nominated Target Problems in the Treatment of Disruptive Behaviors in Youth with Tourette Syndrome

Youth with Tourette syndrome (TS) often exhibit disruptive behaviors. Although improvement data on rating scales support the efficacy of structured psychotherapeutic interventions, there is growing interest in personalized outcome assessments. This report examined parent-nominated target problems (PTPs) as an individualized outcome measure in 48 youth with TS and disruptive behaviors, who participated in one of two randomized psychotherapy trials. At baseline, parents described two primary problems to an independent evaluator who generated a structured narrative for each problem. These narratives were reviewed and updated at endpoint. When rated by five treatment-blind judges, the PTP rating demonstrated excellent reliability and good convergent validity with the Disruptive Behavior Rating Scale (DBRS). The PTP rating exhibited comparable treatment effects to the DBRS, and accounted for additional variance in global treatment outcome. The PTP rating serves a reliable, valid, and sensitive personalized assessment in research trials that provides complementary information to standardized rating scales.